The invention is particularly suited for a blood purification process called peritoneal dialysis (PD) in which a dialyzing solution is placed into a patient's peritoneal cavity and allowed to dwell there for a period of generally four to eight hours. During the course of this dwell period, various waste products, such as urea, will diffuse out of the vascular bed in the peritoneal membrane and into the fluid. Concomitantly, various electrolytes will diffuse from the peritoneal dialysis solution, or dialysate, across the peritoneal membrane and into the blood stream to help restore a proper electrolytic balance.
Most commercially available peritoneal dialysis solutions contain glucose as an osmotic agent to achieve an appropriate osmotic gradient across the membrane and ultrafiltration, the active movement of excess fluid out of the blood and into the PD solution. However, the use of glucose as a component of the dialysate has several disadvantages. Among the disadvantages attendant with the incorporation of glucose into the peritoneal dialysis solution are glucose loading, which may lead, inter alia, to obesity, hyperglycemia, hyperlipidemia.
Another distinct and well known disadvantage of employing glucose in peritoneal dialysis solutions is that at physiologic pH, in the vicinity of 7.4, glucose carmelizes when subjected to sterilizing temperatures of the order of 240.degree. F., decomposing to form 5-hydroxymethyl furfural. To avoid decomposition of the glucose, present practice is to prepare glucose containing dialysate with a pH in the range of 5.0 to 5.9. However, such a relatively low pH has been observed to cause substantial patient discomfort in the form of pain during inflow of the dialysate to the peritoneal cavity.
One of the major causes of change to another form of treatment in patients on peritoneal dialysis is peritonitis. Van Bronswijk, et al. concluded that "the currently available CAPD (continuous ambulatory peritoneal dialysis) solutions are beyond the limits of acid and osmotic tolerance of human phagocytic cells, and may thus compromise the peritoneal defenses of CAPD patients" (van Bronswijk, et al., Dialysis Fluids and Local Host Resistance in Patients on Continuous Ambulatory Peritoneal Dialysis, Eur. J. Clin. Microbiol. Infect. Dis., June 1988, p. 368-373). A similar conclusion with respect to pH was drawn by the authors in Harvey, et al., Effect of Dialysate Fluids on Phagocytosis and Killing by Normal Neutrophils, J. of Clin. Microbiol., Aug. 1987, p. 1424-1427.
At the onset of inflammation associated with peritonitis in patients treated with PD, a large accumulation of neutrophils occurs in the peritoneal cavity. These neutrophils are primarily responsible for eliminating bacteria from the peritoneal cavity. The bactericidal activity of neutrophils is closely linked to the production of the superoxide radical and therefore impaired formation of superoxide is associated with decreased ability of neutrophils to eliminate bacteria and increased susceptibility to peritonitis. In Ing, et al., Suppression of Neutrophil Superoxide Production By Conventional Peritoneal Dialysis Solution, Int. J. of Artif. Organs, vol. 11, no. 5, pp 351-354, it was found that neutrophils exposed to standard acidic PD solutions had a decreased ability to mount a superoxide response while neutrophils exposed to PD solutions having a physiologic pH of 7.4 were able to generate a much larger quantity of superoxide.
Similar results were reported in Duwe, et al., Effects of Composition of Peritoneal Dialysis Fluid On Chemiluminescence, Phagocytosis and Bactericidal Activity In Vitro, Infection and Immunity, July 1981, pp 130-135. All three of the tested functions were shown to be strongly inhibited in peripheral blood leukocytes by PD solution with a pH of 5.2.
A further concern with the low pH solutions is acidosis. In fact, in patients with slowed metabolism, such as those with lactic acidosis, alcoholism and diabetes, acidosis may worsen with the extended use of low pH dialysis solutions.
Current commercial and experimental CAPD solutions do not contain a buffer in the physiologic range. As a result, even when adjusted to pH 7, the pH of these solutions rapidly drops to pH 6 or below. U.S. Pat. No. 3,525,686, issued in 1970, recognized the problem of inflow pain due to low pH and, in an attempt to provide a solution with a more physiologic pH, sorbitol, which does not carmelize under conditions of steam sterilization, was substituted for glucose. However, degradation products of glucose are not the only source of acidity. Other materials such as carbon dioxide from the air and products leaching from the container material may lead to lower pH. Furthermore, since the solution does not contain a buffer, minute amounts of acid material will cause a large drop in pH.
U.S. Pat. No. 4,339,433 discloses polyionic polymers as osmotic agents for CAPD solutions. These agents may simultaneously act as buffers. However, these molecules proved to be toxic to the peritoneum and are not available for chronic administration (Mistry, and Gokal, Alternative Osmotic Agents, Blood Purification, vol. 7, pp 109-114, 1989).
European Patent application No. 277,868 discloses the use of a glycine based peptide for stabilizing bicarbonate solutions for dialysis. The peptide disclosed also acts as an osmotic agent and therefore as an alternative to glucose.
The use of amino acids in PD solutions was first taught in the preliminary communication on page 812 of the Oct. 12, 1968 issue of the Lancet. In that paper, the only concern being investigated was the extent of amino acid and protein loss during peritoneal dialysis. It was noted that protein loss varied from 20-60 g. and amino acid loss was of the order of an additional 13 g. Patients were given a PD solution which included a 5% concentration of a mixture of amino acids. It was concluded that the addition of a mixture amino acids to PD fluids is a simple way to substantially decrease the fall in serum protein and amino acids in patients undergoing PD.
Solutions containing mixture of amino acids as an alternate osmotic agent to glucose have been investigated and it has been shown that these mixtures can function as alternate osmotic agents. They are absorbed well and therefore can serve as an important source of protein in malnourished patients. However, it must always be borne in mind that one of the primary functions of dialysis is to decrease elevated urea levels in patients with end stage renal disease. Administering amino acids, particularly in concentrations greater than 100 mg/kg body weight/day, may markedly increase blood nitrogen and thereby adversely affect blood urea levels. Clearly, one must be very careful to watch blood urea levels while administering amino acids.
This is a concern also because the amino acid solutions proposed to date as alternatives to glucose solutions have been proven to work only with relatively high concentrations of amino acids, generally of the order of 1 to 2%. Generally, solutions with such high concentrations of amino acids cannot be administered on a chronic basis for all exchanges. Such use leads to often substantial side effects.
Mixtures of aminos acids as buffers have been looked at, but only for organ perfusion solution such as for the heart and kidney. European Patent Application No. 12272 discloses such a protective solution with a buffer system composed of histidine, histidine hydrochloride and tryptophane. U.S. Pat. No. 4,761,237 discloses an improved organ protection solution for the heart and kidney which employs the same histidine, histidine hydrochloride and tryptophane buffer system but with the addition of alpha-ketoglutarate to replace lithium ions and to facilitate the partial reduction of the concentration of the buffer system.
However, it should be borne in mind that these publications looked only at the application of the buffer system in the context of its being employed in an organ perfusion solution. Such a solution has as its primary function the improvement of the organ's resistance to damage caused by the total interruption of blood circulation and the resulting ischemia (lack of oxygen) during reconstructive surgery and transplants and is intended for short-term use only. PD solutions are quite different in that their primary functions are to create diffusion gradients across the peritoneum and induce ultrafiltration and they are intended for long-term use.